Feline leukemia virus (FeLV) infection in cats is associated with a variety of disease outcomes, including both proliferative and degenerative diseases. The type and severity of disease in FeLV-infected cats is determined in part by the particular isolate to which they are exposed, suggesting that the genetic basis for these diseases may be elucidated through comparison of different virus variants. One particular isolate of FeLV, called FeLV-FAIDS, has been shown to consistently induce immunodeficiency disease. In FeLV-FAIDS infection, the variants that appear late in infection are more pathogenic than the virus detected early after infection. The variants that predominate in the late stages of FeLV-FAIDS infection are highly T cell tropic, cytopathic viruses. Thus, FeLV infection in cats closely parallels HIV-1 infection in humans, where the viruses isolated from patients with AIDS tend to be T cell tropic cytopathic variants. In the case of HIV-1 infection, the specific contribution of T cell tropic, cytopathic variants to the development of AIDS has been difficult to discern. Thus, FeLV represents a model system which may provide insights into potentially more complex HIV-1 associated diseases. The goal of this proposal is to define functional domains of the virus that regulate T cell-specific replication of immunodeficiency-inducing FeLV variants, and to begin to identify cellular proteins that interact with these determinants. In the FeLV system, the ability of a virus to cause T cell killing in a in vitro assay has been directly correlated with its ability to cause immunodeficiency disease in cats. This provides a cell culture system for the proposed studies that has direct relevance to in vivo infection and disease. Previous studies have shown that the envelope protein is the major determinant for T cell tropism and pathogenicity. Building on this information, we propose a more detailed molecular analysis of the specific sequence changes in the envelope that affect replication and cytopathicity of the virus in T cells. The Specific Aims include: 1) To define the minimal sequence changes in an attenuated immunodeficiency-inducing FeLV variant that affect envelope processing, viral infectivity and cytopathicity. 2) To determine which sequence changes in the extracellular envelope are important for making particular virus variants T cell-tropic and cytopathic. 3) To identify a gene that confers susceptibility to infection with T cell-tropic FelV variants. The emphasis of this research is to define the factors that regulate T cell-specific replication and expression of FeLV, because our long term goals are to better understand diseases, such as immunodeficiency, that result from lymphocyte dysfunction.